This invention relates generally to the generation of pharmaceutical agent particles, and more particularly relates to the use of focused acoustic energy in generating solid particles comprised of a pharmaceutical agent.
Rapid and efficient production of particles, particularly small and/or substantially uniform particles, is needed in a variety of industries. Among other advantages, small, substantially uniform particles possess favorable flow characteristics and exhibit little variation in interparticle behavior. In the pharmaceutical industry, for example, the particle size of a therapeutic agent can affect the dissolution rate, bioavailability and overall stability of the agent in a formulation. Precise control of the particle size of therapeutic agents is particularly important for sustained release applications, where the rate of drug release is related to the size of a particle containing the drug. In addition, pulmonary delivery of a therapeutic agent requires specifically sized particles, generally on the order of about 1 xcexcm to about 7 xcexcm. Particles that are too large may be deposited within the throat, while particles that are too small will be exhaled. Thus, the ability to produce small, uniform particles of a therapeutic agent is critically important in the development of particulate pharmaceutical products.
Various approaches for attaining small and uniform particles have been used. Conventional comminution techniques, e.g., crushing, grinding and milling, rely on mechanical forces to break apart relatively large particles into smaller particles. Air-jet mills and other mills, available from, for example, DT Industries, Bristol, Pa., under the tradename STOKES(copyright), are commonly used by the pharmaceutical industry to decrease the particle size of a bulk therapeutic agent into a range suitable for pharmaceutical applications. One drawback to such mechanical comminution techniques, however, is that some therapeutic agents, particularly proteins and other therapeutic biomolecules, are damaged during the process. Another drawback of mechanical comminution is the wide distribution of particle sizes produced by these techniques. Among other problems, large variations in the size of particles limit the ability to produce sustained-release formulations and waste large amounts of therapeutic agents intended, for example, for inhalation. Although sieving a comminuted therapeutic agent through an appropriate mesh screen provides a more narrow particle size distribution, large quantities of particles not having the desired size are wasted and the potential for contamination is increased, as the therapeutic agent must contact additional surfaces.
Other techniques for producing pharmaceutical particles include conventional recrystallization methods. In such methods, the therapeutic agent is initially dissolved in a suitable solvent. In one approach, the temperature of the solution is changed so that the solubility of the solute is decreased. In another approach, a second solvent, an xe2x80x9cantisolvent,xe2x80x9d is added so that the solubility of the solute is decreased. In both approaches, the solute precipitates or crystallizes out of the solution due to reduced solubility in the altered solution. These methods, however, often require toxic solvents, result in wet particles (that require further processing, e.g., drying), and may produce particles having variable sizes.
Supercritical fluid technology has solved some of these problems. One method for using this relatively new technology is called the rapid expansion of supercritical solutions or xe2x80x9cRESSxe2x80x9d method. See Tom et al. (1991) Biotechnol. Prog. 7(5):403-411. In the RESS method, the solute of interest, e.g., a pharmaceutical agent, is first solubilized in a supercritical fluid, i.e., a fluid at a temperature and pressure greater than its critical temperature (Tc) and critical pressure (Pc) Generally, the supercritical fluid is carbon dioxide, although other fluids are available. The solution is then rapidly passed through a nozzle that is connected to a relatively low-pressure medium. The sudden depressurization of the solution as it passes into the relatively low-pressure medium causes the supercritical fluid to expand, i.e., the density of the supercritical fluid decreases, reducing the ability of the supercritical fluid to solubilize the therapeutic agent. As a direct consequence of the reduced solubility, a supersaturated solution develops, which, in turn, causes the solute agent to precipitate or crystallize out in very small particles.
A variation of this idea is to prepare a solution of a therapeutic drug in a conventional solvent, and then spray the solution through a nozzle into a supercritical fluid that acts as an anti-solvent. When the two fluids make contact, a rapid volume expansion occurs, reducing solvent density and solvent capacity, in turn increasing supersaturation, solute nucleation and particle formulation. This method is commonly referred to as gas anti-solvent recrystallization or xe2x80x9cGAS.xe2x80x9d See, for example, Debenedetti et al. (1993) J. Control. Release 24:27-44 and PCT WO 00/37169 to Merrifield. This process has been applied to various proteins to produce particle sizes of about 5 xcexcm. See European Patent No. 0 542 314.
Although use of supercritical fluid technology offers the capability of producing relatively small particles of uniform size, it is not without drawbacks. One problem associated with these supercritical methods is the reliance on nozzles and tubes for delivering the solutions. Nozzles are known to wear down over time, altering the geometry of the equipment and affecting the size of the droplets formed. In addition, nozzles may become blocked during use, when, for example, particles agglomerate upon rapid expansion within the nozzle bore. In addition, nozzles and associated components require cleaning and may contaminate solutions when not properly maintained.
Furthermore, the droplet sizes of the solutions (both supercritical and conventional solutions) produced by methods relying on nozzles are relatively varied. As a result there will be a large variance of the surface tension between droplets of different sizes. At the sizes required for supercritical methods, the differences in surface tension between droplets causes large variations in crystallization kinetics and growth. These differences result in differently sized particles. Although U.S. Pat. No. 5,874,029 to Subramaniam et al. discusses methods for producing small-sized droplets using nozzles, the methods still suffer from the inability to effectively and consistently produce droplets of uniform size.
Thus, there is a need in the art for an improved particle formation technique wherein particle formation is highly reproducible, controllable and predictable, and substantially uniform particle size can be achieved. An ideal method would minimize or eliminate contact of the particle-forming fluid(s) with surfaces of process equipment or contaminants adsorbed thereon. The present invention addresses the aforementioned need in the art by using focused acoustic energy to eject particle-forming droplets from a pharmaceutical agent solution.
Accordingly, it is a primary object of the invention to address the aforementioned need in the art by providing a novel method and device for generating pharmaceutical agent particles using focused acoustic ejection technology.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect, then, the invention provides a method and device for generating solid particles of pharmaceutical agents using focused acoustic energy. A solution of the pharmaceutical agent is provided in a solvent, which may be an aqueous fluid, a nonaqueous fluid, or a supercritical fluid. Focused acoustic energy is used to eject a droplet of the solution, which is then directed into or through an antisolvent that upon admixture with the solution droplet causes the pharmaceutical agent in the droplet to precipitate. The solid particle that results is then collected. In a preferred embodiment, the solvent is an aqueous or organic liquid, and the antisolvent is a supercritical fluid. It will be appreciated that the pharmaceutical agent must be less soluble in the antisolvent than in the solvent, and substantially inert in both the solvent and antisolvent.
Generally, the solution and the antisolvent will both be present in the reservoir, with the reservoir being covered or otherwise enclosed so as to provide the xe2x80x9ccontained space.xe2x80x9d The particles resulting from the ejected droplets are collected on a surface within the contained space, typically on a surface within the reservoir enclosure.
With supercritical antisolvents, expansion of the solution droplet upon ejection into a lower pressure supercritical medium causes rapid depressurization of the droplet, supersaturation thereof, and precipitation of virtually contaminant-free particles, ideally in crystalline form.
The method is advantageous in a number of respects. For example, the method:
can be used to prepare very small particles, on the order of microns or even nanometers in diameter;
gives rise to particles of substantially uniform size, i.e., having a narrow particle size distribution;
can be used to prepare different crystal structures of a single molecular entity (i.e., by selection of a proper solvent and/or solvent-cosolvent combination);
is highly reproducible, controllable and predictable;
can be readily scaled up, but is also quite effective with very small quantities of both pharmaceutical agents and fluids, making it ideal for manufacturing particles of rare and/or expensive drugs;
is a single-step process, in contrast to the many multi-step processes of the prior art; and
is suitable for use with a wide range of pharmaceutical agents and excipients.
In another aspect, the invention provides a device for carrying out the aforementioned method. The device comprises: a reservoir containing a solution of the pharmaceutical agent in a solvent; an antisolvent in a contained space in fluid communication with the solution in the reservoir such that droplets ejected from the solution are directed into the antisolvent; an acoustic ejector comprising an acoustic radiation generator for generating acoustic radiation and a focusing means for focusing the acoustic radiation at a focal point within the solution in the reservoir so as to eject a droplet therefrom; and, optionally, a means for positioning the ejector in acoustic coupling relationship to the reservoir.